Cancer is caused by the progressive accumulation of multiple genetic abnormalities in proto-oncogenes and tumor suppressor genes (1). The appreciation that specific cancers are associated with discrete combinations of genetic events suggests that a highly effective and specific form of cancer therapy would be to target the repair, replacement or inactivation of oncogenes or tumor suppressor genes (1). Nevertheless, this assumes both that cancer as a multi-step process is generally reversible and that cancer cells will not be able to compensate for the repair of a single abnormal genetic event. The C-MYC proto-oncogene is commonly activated in specific human neoplasia and may be an excellent target for the therapy of cancer. The goal of the proposed research is to determine if the targeted inactivation of C-MYC will be effective as a treatment for cancer. Preliminary data described in this proposal demonstrate that C-MYC induced tumorigenesis of the immortal cell line Rat-1a is not reversible with inactivation of C-MYC. Perhaps accounting for this observation, Rat-1a cells become rapidly genomically unstable with C-MYC activation. Experiments will be performed to determine if C-MYC induces tumorigenesis reversible with C-MYC inactivation in other rodent and human cell lines and in transgenic mice, to determine if C-MYC activation generally induces genomic instability, to determine if other oncogenes, genes transcriptionally regulated by C-MYC, and genes that are associated with acceleration with C-MYC tumorigenesis induce genomic instability, and to determine in cases where tumors persist despite C-MYC inactivation, the genetic events responsible for a persistent malignant phenotype. If C-MYC activation generally induces tumorigenesis that is reversed with C-MYC inactivation, then it will be concluded that C-MYC inactivation is likely to be an effective therapy for C-MYC induced cancers. If this is not the case, the genetic events responsible for a persistent tumorigenic phenotype will be determined. The targeted the repair of these genetic events may be more likely to be effective in the treatment of C-MYC induced human cancers. The results obtained from these studies will not only provide a better understanding of the mechanism of C-MYC induced tumorigenesis and C-MYC induced genomic instability, but will identify the best targets for the therapy of C-MYC induced cancers.